1、Neurocircuitry of Addiction: View from the Dark Side,George F. Koob, Ph.D. Professor and Chair Committee on the Neurobiology of Addictive Disorders The Scripps Research Institute La Jolla, California,Koob, G.F. and Le Moal, M. Addiction and the anti-reward system. Annual Review of Psychology, 59 (20
2、08)29-53Koob, G. F. and Volkow. N. D. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010) 217-238,“When people talk about drugs, they assume people take drugs because they enjoy it,” Williams told the Toronto Star. “But really, its no different from overeating or watching too much
3、 television or drinking too much. You take drugs to make yourself feel better, to fill a hole.”-Ricky Williams-Byline Damien Cox, Toronto Star, May 29, 2006,Addiction is a Reward Deficit Disorder,Reward neurotransmission is compromised. Brain reward systems are hypoactive during acute withdrawal, re
4、main hypoactive with repeated withdrawal and during protracted abstinence.Anti-reward neurotransmission is recruited- Brain stress systems are activated during acute withdrawal, sensitize with repeated withdrawal and remain activated during protracted abstinence.,Progression of Drug Dependence,From:
5、 Heilig M and Koob GF, Trends Neurosci, 2007, 30:399-406.,From: Koob GF, Alcohol Clin Exp Res, 2003, 27:232-243.,Positive and Negative Reinforcement- Definitions,Positive Reinforcement defined as the process by which presentation of a stimulus (drug) increases the probability of a response (non depe
6、ndent drug taking paradigms). Negative Reinforcement defined as a process by which removal of an aversive stimulus (negative emotional state of drug withdrawal) increases the probability of a response (dependence-induced drug taking),Stages of the Addiction Cycle,Neurobiology of Addiction,Koob, G. F
7、. and Volkow. N. D. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010) 217-238,Binge/Intoxication Stage,Koob, G. F. and Volkow. N. D. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010) 217-238,Cocaine Self-Administration,From: Caine SB, Lintz R and Koob GF. in
8、 Sahgal A (ed) Behavioural Neuroscience: A Practical Approach, vol. 2, IRL Press, Oxford, 1993, pp. 117-143.,Effects of 6-OHDA Lesions of the Nucleus Accumbens on Cocaine Self-administration in Rats,From: Roberts DCS, Koob GF, Klonoff P and Fibiger HC, Pharmacol Biochem Behav, 1980, 12:781-787.,Conv
9、erging Acute Actions of Drugs of Abuse on the Ventral Tegmental Area and Nucleus Accumbens,From: Nestler EJ, Nat Neurosci, 2005, 8:1445-1449.,Withdrawal/Negative Affect Stage,Koob, G. F. and Volkow. N. D. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010) 217-238,Affective Dynami
10、cs Produced by Drug Administration in Non Dependent versus Dependent Subjects,From: Solomon RL, American Psychologist, 1980, 35:691-712.,Reward Transmitters Implicated in the Motivational Effects of Drugs of Abuse,Dopamine “dysphoria” Opioid peptides . pain Serotonin “dysphoria” GABA anxiety, panic
11、attacks,Dopamine Opioid peptides Serotonin GABA,Positive Hedonic Effects,Negative Hedonic Effects of Withdrawal,Protocol for Drug Escalation,All Rats (n=24): 2-hr SA session Fixed Ratio 1 0.25 mg cocaine/injection,1) Initial Training Phase,Short Access (n=12) 22 x 1-hr SA session,2) Escalation Phase
12、,Long Access (n=12) 22 x 6-hr SA session,Cocaine doses (g): 0, 15.6, 31.2, 62.5, 125, 250,3) Dose-Effect Study,Protocol from: Ahmed SH and Koob, Science, 1998, 282:298-300.,Change in Brain Stimulation Reward Thresholds in Long-Access (Escalation) vs. Short-Access (Non-Escalation) Rats,From: Ahmed SH
13、, Kenny PJ, Koob GF and Markou A, Nature Neurosci, 2002, 5:625-627.,Effect of a-flupenthixol on Cocaine Self-Administration in Escalated and Non-Escalated Animals,From: Ahmed SH and Koob GF, unpublished results.,Decreased Dopamine D2 Receptor Activity in a Cocaine Abuser,From: Volkow ND, Fowler JS,
14、Wang GJ, Hitzemann R, Logan J, Schlyer DJ, Dewey S and Wolf AP, Synapse, 1993, 14:169-177.,Affective Dynamics Produced by Drug Administration in Non Dependent versus Dependent Subjects,From: Solomon RL, American Psychologist, 1980, 35:691-712.,Anti-Reward Transmitters Implicated in the Motivational
15、Effects of Drugs of Abuse,Dynorphin “dysphoria” CRF stress Norepinephrine stress,CNS Actions of Corticotropin-Releasing Factor (CRF),Major CRF-Immunoreactive Cell Groups and Fiber Systems in the Rat Brain,From: Swanson LW, Sawchenko PE, Rivier J and Vale W, Neuroendocrinology, 1983, 36:165-186.,CRF
16、Produces Arousal, Stress-like Responses, and a Dysphoric, Aversive State,Sampling of Interstitial Neurochemicals by in vivo Microdialysis,Allows sampling of neurochemicals in conscious animals (correlate brain chemistry with behavior). Implanted so that semi-permeable probe tip is in specific brain
17、region of interest. Substances below the membrane MW cutoff diffuse across membrane based on concentration gradient. Both neurochemical sampling and localized drug delivery are possible.,Collaborators: Dr. Friedbert Weiss, Dr. Larry Parsons, Dr. Emilio Merlo-Pich, Dr. Regina Richter,Withdrawal-induc
18、ed Increases in Extracellular Levels of CRF,Conditioned Place Aversion Produced by One Pairing of Naloxone in Morphine-Dependent Rats,From: Gracy KN, Dankiewicz LA and Koob GF, Neuropsychopharmacology, 2001, 24:152-160.,CRF1 Specific Antagonists,Effects of Antalarmin on Place Aversion Induced by Nal
19、oxone-Precipitated Morphine Withdrawal,From: Stinus L, Cador M, Zorrilla EP and Koob GF, Neuropsychopharmacology, 2005, 30:90-98.,Competitive CRF Antagonist Injected into the Amygdala Blocks Conditioned Place Aversion to Opiate Withdrawal,From: Heinrichs SC, Menzagi F, Schulteis G, Koob GF and Stinu
20、s L, Behav Pharmacol, 1995, 6:74-80.,Increase in Brain Reward Thresholds during Escalation in Heroin Intake in Rats with Prolonged Access to Heroin (23-hr/day),From: Kenny PJ, Chen SA, Markou A and Koob GF Journal of Neuroscience 26 (2006) 5894-5900,CRF1 Antagonist R121919 Decreases Heroin Self-Admi
21、nistration in Rats with 12 h Extended Access,From: Greenwell TN, Funk CK, Cottone P, Richardson HN, Chen SA, Rice K, Lee MJ, Zorrilla EP and Koob GF, Addict Biol, in press.,Role of Corticotropin-releasing Factor in Dependence,CRF antagonist effects on withdrawal-induced anxiety-like responses,Drug,C
22、ocaine Opioids Ethanol Nicotine 9-tetrahydrocannabinol,Withdrawal-induced changes in extracellular CRF in CeA, ,CRF antagonist effects on dependence-induced increases in self-administration, nt,CRF antagonist reversal of stress-induced reinstatement, nt,From: Koob, G.F. 2008 Neuron 59:11-34,Preoccup
23、ation/Anticipation “Craving” Stage,Koob, G. F. and Volkow. N. D. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010) 217-238,Reward Craving-Type 1,“Craving”- induced by stimuli that have been paired with drug self-administration such as environmental cuesAn animal model of craving
24、- type 1 is cue induced reinstatement where a cue previously paired with access to drug reinstates responding for a lever that has been extinguished.Neurobiological substrates include glutamatergic projections from medial prefrontal cortex and basolateral amygdala to nucleus accumbens,Reinstatement,
25、Reinstatement of Drug (Alcohol) Seeking with Drug-Associated Contextual Stimuli,Daily Sessions of Self-Administration,Role of Glutamate and Dopamine Neurotransmission in Relapse to Drug-Seeking Behavior,From: Cornish JL and Kalivas PW, J Addict Dis, 2001, 20:43-54.,Relief Craving-Type 2,State of pro
26、tracted abstinence in subjects with addiction or alcoholism weeks after acute withdrawal.Conceptualized as a state change characterized by anxiety and dysphoria or a residual negative emotional state that combines with Craving-Type 1 situations to produce relapse to excessive drug takingAnimal model
27、s of Craving-Type 2 include stress-induced reinstatement and increased drug taking in animals during protracted abstinenceNeurobiological substrates include residual activation of brain stress systems including corticotropin releasing factor and norepinephrine in the extended amygdala,Brain Circuits
28、 Critical for Stress-Induced Reinstatement of Drug-Seeking Behavior,From: Shaham Y, Shalev U, Lu L, De Wit H and Stewart J, Psychopharmacology, 2003, 168:3-20.,Stress and Anti-stress Neurotransmitters Implicated in the Motivational Effects of Drugs of Abuse,Corticotropin-releasing factor,Norepinephr
29、ine,Vasopressin,Orexin (hypocretin),Dynoprhin,Neuropeptide Y,Nociceptin (orphanin FQ),Substance P,Brain Arousal-Stress System Modulation in the Extended Amygdala,From: Koob, G.F. 2008 Neuron 59:11-34,Regulation of the Mesolimbic Dopamine Circuit and Hypothalamus by the Extended Amygdala,Neuroplastic
30、ity in Brain Circuits associated with the Development of Addiction,From: Koob and Volkow, Neurocircuitry of addiction, Neuropsychopharmacology Reviews, in press,Neuroplasticity with Increasing Use,Compulsivity Loss of Control,Mesolimbic DA,Nucleus Accumbens,Dorsal Striatum,Prefrontal Cortex,Extended
31、 Amygdala,Allostatic Change in Emotional State associated with Transition to Drug Addiction,Adapted from: Koob GF and Le Moal M, Neuropsychopharmacology, 2001, 24:97-129.,Key Findings and Conclusions,Acute reinforcing effects of drugs of abuse depend on neurochemical substrates such as GABA, opioid
32、peptides, serotonin, glutamate and dopamine in the ventral striatum of the basal forebrain.Acute withdrawal from all major drugs of abuse produces decreases in reward function, increases in stress-like responses and increases in CRF in the amygdala that are of motivational significance“Craving” (Pre
33、occupation/anticipation stage of addiction cycle)- involves a significant glutamate system dysregulation and a brain stress component also mediated by CRF systems in the extended amygdalaCompulsive drug use associated with dependence is mediated by not only loss of function of reward systems but rec
34、ruitment of brain stress systems such as corticotropin releasing factor, norepinephrine and dynorphin in the extended amygdalaBrain-arousal stress systems in the extended amygdala- may be key components of not only for the negative emotional states that drive dependence on drugs of abuse but also ma
35、y overlap with the negative emotional components of other psychopathologies,Neurobiology of Drug Addiction Koob Laboratory,Post-Doctoral Fellows Cindy Funk Brendan Walker Tom Greenwell Sandy Ghozland Chitra Mandyam Dong Ji Candice ContetLaura Orio Nick Gilpin Sunmee Wee Kaushik Misra Scott Edwards L
36、eandro Vendruscolo,Special thanks to: Mike Arends (Senior Research Assistant),Research Assistants Bob Lintz Richard Schroeder Elena Crawford Molly Brennan Maury Cole Tess Kimber Yanabel Grant,Administrative Assistants Lisa Maturin Mellany Santos Marisa Gallego,Staff Scientist Heather Richardson Olivier George,Support from: National Institute on Alcohol Abuse and Alcoholism National Institute on Drug Abuse National Institute of Diabetes and Digestive and Kidney Diseases Pearson Center for Alcoholism and Addiction Research,Visiting Professors Choon-Gon Jang Charles Heyser,
